Wnt5a is a non-canonical secreted glycoprotein of the Wnt family that plays an important role in cancer development and progression.
Peptides derived from Wnt5a, including the N-formylated hexapeptide Foxy5, have been described earlier, i.a. in WO 01/32708 and WO 2006/130082. These peptides have been shown to be agonists of Wnt5a signaling. The use of such a peptide in a mouse breast cancer model has demonstrated its ability to significantly inhibit the metastatic spread from the primary tumor inoculated and growing in a mammary fat pad. In WO 2010/019103 it has been shown that by modifying such peptides in a certain way it is possible to change the agonist function to that of an antagonist, and further that such antagonists may be used in treatment of melanoma and gastric cancer.
Previous studies report that Wnt5a is upregulated in prostate cancer and suggested that Wnt5a affects migration and invasion of prostate tumor cell.
Prostate cancer (PCa) is the leading cancer affecting men of all races and the second most leading cause of death in developed countries [1]. Androgens and the androgen receptor (AR) play critical roles not only in normal development, growth and function of the prostate gland but also in carcinogenesis and progression of PCa [2]. Initially, PCa cells are commonly AR dependent for their growth and survival, and hence respond to androgen deprivation therapy (ADT), but in later stages PCa cells become androgen-insensitive, and fatal castration-resistant prostate cancer (CRPC) develops [3]. The molecular mechanisms responsible for transition into CRPC are poorly understood, however, the most consistent change associated with castration resistant growth in global gene expression profiles of PCa xenografts was an increase in the AR mRNA levels [4]. Increased expression of AR is considered to be a key feature of CRPC and it has been demonstrated as a consequence of either mutation or amplification of AR or by increased expression caused by deregulated growth factors or various co-regulators [5]. Although we have access to prognostic factors in PCa, including Gleason grade, TNM stage, surgical margin status and serum PSA levels, there is an urgent need to identify novel biomarkers, which can significantly improve, either alone or in combination of other biomarkers, our ability to predict outcome in PCa patients. Previous studies have suggested a possible relationship between AR and Wnt-β-catenin signaling pathways during the development and progression of PCa [6,7].
Recently, attention has been drawn to the role of Wnt proteins and Wnt signaling in PCa. The name Wnt comes from “wingless-related MMTV integration site” and was originally suggested by Nusse and co-workers in 1991 [8]. Wnt proteins constitute a family of nineteen secreted glycoproteins that play important roles during development and in cell fate specification, cell migration and cell polarity [9,10]. Wnt proteins can be classified into at least two subfamilies; canonical Wnts that promote β-catenin-mediated transcription and non-canonical Wnts. Wnt signaling occur in an auto- or paracrine fashion through binding of secreted Wnt molecules to seven transmembrane Frizzled receptor proteins (Fz) in the absence or presence of co-receptors such as LRP 5/6 and ROR [10]. Several Wnt signaling components have also been implicated in genesis of human cancers; overexpression of Wnt-1 was observed in mammary epithelial adenocarcinoma [11] and in several PCa cell lines and PCa tissues. Wnt-1 expression positively correlated with Gleason score, β-catenin and with serum PSA levels [12]. In addition, based on the determination of Wnt5a mRNA levels in prostate tumors it has been suggested that abnormal expression of the non-canonical Wnt5a is involved in PCa [13].
Wnt5a, one of the most studied non-canonical Wnts, is an essential Wnt protein in inducing and controlling the Wnt/planar cell polarity (PCP) and the Wnt/Ca2+ pathways [14,15]. In addition, Wnt5a has not only been demonstrated to counteract the Wnt/β-catenin pathway but also, in specific contexts, to activate this pathway [16]. The possibility of Wnt5a to induce different downstream signaling events can at least in part explain the presence of reports suggesting an ambiguous nature of Wnt5a; having either a tumor suppressor or tumor promoting function depending on context and tumor type [16]. Previous studies have shown that Wnt5a is downregulated in certain malignancies including colorectal cancer (protein expression) [17], neuroblastoma (mRNA levels) [18], invasive ductal breast carcinomas (protein expression) [19,20] and leukaemias (mRNA levels) [21], indicating a tumor suppressing effect of Wnt5a.
Interestingly, other reports have instead suggested an oncogenic effect of Wnt5a primarily based on an upregulation in breast cancer cells (mRNA levels) [22], gastric cancer (protein expression) [23], melanoma (protein expression) [24], lung cancer and prostate cancer (mRNA expression) [13]. Aberrant gene and protein expression of Wnt5a in PCa and possible underlying molecular mechanisms have been described in previous reports [13, 25, 26, 27]. In a recent study, based on the Affymetrix studies of normal prostate epithelial and cancer cell lines, Wang et al showed that increased transcription of the Wnt5a gene in PCa was due to hypomethylation; suggesting that epigenetic regulation of Wnt5a expression may be of importance in PCa progression [28]. Any conclusion made from data from an Affymetrix analysis without a simultaneous analysis of Wnt5a protein expression is dangerous since the Wnt5a mRNA has a long untranscribed 3′-region open for translational regulation. Data supporting such a translational regulation of Wnt5a protein expression has previously been reported [19,29].
Recent studies have shown increased Wnt5a and protein levels in PCa compared to benign tissue [25,26]. Yamamoto et al demonstrated in vitro that knockdown of Wnt5a reduced the invasive properties of DU145, and over-expression of Wnt5a stimulated invasion of PC3 cells [25]. In contrast, Wang Q and co-workers demonstrated that recombinant Wnt5a did not induce an increased motility in the same PC3 cells [26]. In addition, it has been shown by immunohistochemistry (IHC) that Wnt5a expression correlated with Gleason score≧8 in 24 patients from a cohort of 98 PCa patients that had undergone radical prostatectomy. This could indicate that Wnt5a promotes aggressiveness, since patients with low Wnt5a levels had a better relapse-free survival compared to patients with high Wnt5a levels [25].